Colorectal cancer (CRC) is a major cause of cancer mortality, with poor outcomes driven by the tumor microenvironment (TME). Heterogeneous cancer-associated fibroblasts (CAFs) remodel the extracellular matrix (ECM), suppress immunity, and secrete cytokines that promote progression and resistance. As both barriers and therapeutic targets, CAFs are central to strategies aimed at overcoming treatment limitations in CRC.We examine how CAF heterogeneity, with predominantly pro-tumorigenic but occasionally tumor-restraining functions, contributes to drug delivery resistance. This review highlights nanodrug delivery systems that integrate CAF targeting as a promising strategy to enhance therapeutic efficacy. Approaches include passive and active targeting of ECM degradation to improve drug penetration, advanced carriers for CAF reprogramming, CAF markers, and multifunctional platforms combining chemo- and immunotherapy. Literature was identified through PubMed, Web of Science, Scopus, and ClinicalTrials.gov searches up to September 2025, focusing on CAF biology, nanodrug delivery, and CRC translation.CAF-targeted nanodrug delivery offers a transformative opportunity to address long-standing barriers in CRC therapy. Future advances will depend on the integration of multi-omics CAF subtyping, rational combination regimens, and clinically scalable nanocarriers to translate these strategies into a lasting clinical benefit.